During embryo implantation and placentation, cytotrophoblast cells of the conceptus proliferate and migrate. Growth factors induce cytotrophoblasts to replicate, and to increase the number of cytotrophoblasts that migrate into the uterine endometrium. During this process cytotrophoblasts sequentially attach (adhere) and detach (de-adhere) from surrounding cells and extracellular matrix. Migrating cytotrophoblasts also secrete extracellular matrix to which they can adhere, as well as proteolytic enzymes that degrade the extracellular matrix from which they detach and through which they migrate. Similar processes occur during differentiation of stem cells in the embryo, fetus, child, and adult.
In many biological processes, cells change or differentiate from one cell type to another in response to growth factor polypeptides and glycoproteins. In mammals, these growth factors may either originate from the progenitor cell undergoing differentiation (autocrine mechanism) or from neighbouring cells (paracrine mechanism). These biological processes include those that occur during normal mammalian development in which cells of different types in the conceptus change into other cell types that form the placenta, tissues and organs of the embryo, the fetus, and eventually the adult.
The differentiation pathway of cytotrophoblasts and embryonic and adult stem cells includes migration from one site to another. This can include invasion by the migrating cells into a tissue or organ comprised of or constructed by cells of other types or lineages.
Cells of all types proliferate and migrate during organogenesis and to increase the size of the tissue during normal development and growth in embryonic/fetal life and throughout childhood.
Embryonic stem cells are pluripotent cells derived from the inner cell mass of the early mammalian embryo from which all cell types of the embryo and all endodermal and mesodermal cells in the extra-embryonic tissues are derived. In vivo they differentiate in a low oxygen environment during the first third of pregnancy in humans and other mammals.
Adult stem cells are pluripotent cells found in all mammalian tissues from which many or all cell lineage types of the body may differentiate.
Cytotrophoblast cells are derived from extra-embryonic ectodermal cells of the conceptus, which comprise the trophectoderm of the blastocyst. Cytotrophoblast cells are therefore an epithelial cell type. Cytotrophoblast cells migrate into the endometrium of the maternal uterine decidua to form the placenta. Within the exchange region of the placenta cytotrophoblast cells, known as villous cytotrophoblasts, retain their epithelial phenotype. However, invasive cytotrophoblasts, also known as extravillous cytotrophoblasts, have undergone epithelial-mesenchymal transition, a process which allows them to assume a migratory phenotype. Invasion of the maternal decidua by cytotrophoblast cells is terminated by fusion of cytotrophoblast cells to form multinucleate cells called placental bed giant cells.
Under specific conditions cytotrophoblasts and stem cells, both embryonic and adult, are able to synthesise and secrete insulin-like growth factor II (IGF-II). These processes occur in a low oxygen environment.
Since the IGF-II gene is imprinted and expressed by the paternal allele, the paternal genotype is important in determining the capacity of the placenta, the genotype of which is a combination of the paternal and maternal genotypes, to synthesise IGF-II. It is known that there are polymorphisms in the IGF-II gene which may determine the capacity of tissues to synthesise IGF-II. Since the placenta synthesises abundant IGF-II it was postulated that mutations in the IGF-II gene may lead to pre-eclampsia. A common Apa I restriction fragment length polymorphism in exon 9 of the IGF-II gene was investigated as a possible mutation which causes pre-eclampsia (Bermingham et al. 2000). It was unequivocally shown that this polymorphism in the IGF-II gene is not involved in pre-eclampsia. The authors concluded that IGF-II does not play a role in the aetiology of pre-eclampsia. As there are other polymorphisms in this gene and neighbouring genes which determine the capacity of the placenta to synthesise IGF-II, and hence its capacity to invade the uterine decidua and establish optimal placental function, we claim that IGF-II plays a determining role in pre-eclampsia.
Expression of IGF-II is affected by a functional polymorphism of the insulin (INS) variable number of tandem repeats (VNTR) locus in humans. In Caucasians, the INS VNTR micro satellite divides into two classes of alleles which vary in size. Class I alleles (26-63 repeat units) have been strongly associated with insulin dependent diabetes mellitus (Bennett & Todd 1996), while Class III alleles protect against IDDM but are associated with non-insulin dependent diabetes mellitus (Ong et al. 1999). The INS VNTR has been shown to be a long range control element for both insulin and IGF-II.
All nucleated cells in the body have the capacity to detect oxygen concentration and respond accordingly. Chronic reductions in oxygen concentration within the cell result in new gene expression which is mediated by several transcription factors. Hypoxia inducible factor-1 (HIF-1) is an oxygen-sensitive transcription factor which regulates gene expression in response to low cellular oxygen concentration. HIF-1 activates the transcription of a variety of target genes whose protein products are involved in angiogenesis, cell proliferation and viability, and vascular remodelling. HIF-1, also known as ARNT, is constitutively expressed and must bind to HIF-1, which is regulated by hypoxia (Huang et al. 1996), before binding to DNA as a heteromeric complex (Wang et al. 1995). IGF-II is a target gene for HIF-1 and is thought to be both regulated by, and a regulator of, HIF-1 (Feldser et al. 1999). Feldser et al. reported that in normoxic conditions insulin, IGF-I and IGF-II all induce HIF-1 protein expression resulting in transcription of its target genes including IGF-II, IGFBP-2 and IGFBP-3. When human chorionic villous explants were cultured in 2% O2 and compared with those cultured in 20% O2 cytotrophoblast proliferation was increased nearly 3-fold (Genbacev et al. 1997). In cultured human villous explants HIF-1 transcription was stimulated by low oxygen tension (3% O2) and cytotrophoblast proliferation ensued (Caniggia et al. 2000).